TNF-α converting enzyme (TACE) catalyzes the formation of TNF-α from membrane bound TNF-α precursor protein. TNF-α is a pro-inflammatory cytokine that is believed to have a role in rheumatoid arthritis [Shire, M. G.; Muller, G. W. Exp. Opin. Ther. Patents 1998, 8(5), 531; Grossman, J. M.; Brahn, E. J. Women's Health 1997, 6(6), 627; Isomaki, P.; Punnonen, J. Ann. Med. 1997, 29, 499; Camussi, G.; Lupia, E. Drugs, 1998, 55(5), 613], Crohn's disease [Van Assche, G.; Rutgeerts, P.; Exp. Opin. Invest. Drugs, 2000, 9, 103; Rutgeerts, P.; Baert, F. Drugs of Today, 2000, 36(Suppl. G, Doctor in Focus), 59], psoriatic arthritis [Kreuger, G.; Callis, K.; Archives of Dermatology, 2004, 140, 218], psoriasis [Kristensen, M.; Chu, C. Q.; Eedy, D. J.; et al.; Clin. Exp. Immunol., 1993, 94, 354], vasculitis [Lorenz, H.-M.; Kalden, J. R.; Arthritis Res., 2002, 4(suppl 3), S17], ankylosing spondylitis [Wendling, D.; Toussirot, E.; Exp. Opin. Pharmacotherapy, 2004, 5, 1497], septic shock [Mathison, et. al. J. Clin. Invest. 1988, 81, 1925; Miethke, et al. J. Exp. Med. 1992, 175, 91; Robertshaw, H. J.; Brennan, F. M.; Br. J. Anaesth., 2005, 94, 222], graft rejection [Piguet, P. F.; Grau, G. E.; et al. J. Exp. Med. 1987, 166, 1280], cachexia [Beutler, B.; Cerami, A. Ann. Rev. Biochem. 1988, 57, 505], anorexia, inflammation [Ksontini, R.; MacKay, S. L. D.; Moldawer, L. L. Arch. Surg. 1998, 133, 558], congestive heart failure [Packer, M. Circulation, 1995, 92(6), 1379; Ferrari, R.; Bachetti, T.; et. al. Circulation, 1995, 92(6), 1479; Feldman, A. M.; Combes, A.; Wagner, D,; J. Am. Coll. Cardiol., 2003, 35, 537; Mamoru, S.; Iwasaka, J.; Nakamura, M.; et al.; Eur. J. Heart Failure, 2004, 6, 869], post-ischaemic reperfusion injury [Gilles, S.; Zahler, S.; Welsch, U.; et al.; Cardiovascular Res., 2003, 60, 608], inflammatory disease of the central nervous system [Moro, M. A.; Hurtado, O.; Cardenas, A; et al.; Neurosignals, 2003, 12, 53], inflammatory bowel disease and ulcerative colitis [Colon, A. L.; Menchen, L. A.; Hurtado, O.; De Cristobal, J.; Lizasoain, I.; Leza, J. C.; Lorenzo, P.; Moro, M. A.; Cytokine, 2001, 16, 220; Kirkegaard, T.; Pedersen, G.; Saermark, T.; Brynskov, J.; Clin. Exp. Immunol.; 2004, 135, 146], insulin resistance and diabetes [Hotamisligil, G. S.; Shargill, N. S.; Spiegelman, B. M.; et. al. Science, 1993, 259, 87; Hotamisligil, G. S.; Spiegelman, B. M.; Diabetes, 1994, 43, 1271; Morimoto, Y.; Nishikawa, K.; Ohashi, M. Life Sci., 1997, 61, 795], chronic obstructive pulmonary disease (COPD) and asthma [Trifilieff, A.; Walker, C.; Keller, T.; Kottirsch; Neumann, U.; Brit. J. Pharmacol., 2002, 135, 1655], stroke [Wang, X.; Feuerstein, G. Z.; Xu, L.; et al.; Mol. Pharmacol., 2004, 65, 890; Wang, X.; Xu, L.; Feuerstain, G. Z.; et al. Circulation, 2003, 108 (17 Supp.), iv-103; Hallenback, J. M.; Nature Medicine, 2002, 8, 1363. ], pneumococcal meningitis [Meli, D. N.; Loeffler, J. M.; Baumann, P. et al.; J. Neuroimmunology, 2004, 151, 6], tumor metastasis [Nelson, A. R.; Fingleton, B.; Rothenberg, M. L.; et al.; J. Clin. Oncol., 2000, 18, 1135], multiple sclerosis [Clements, J. M.; Cossins, J. A.; Wells, G. M.; et al.; J. Neuroimmunol., 1997, 74, 85]] and HIV infection [Peterson, P. K.; Gekker, G.; et. al. J. Clin. Invest. 1992, 89, 574; Pallares-Trujillo, J.; Lopez-Soriano, F. J. Argiles, J. M. Med. Res. Reviews, 1995, 15 (6), 533], in addition to its well-documented antitumor properties [Old, L. Science, 1985, 230, 630]. For example, research with anti-TNF-α antibodies and transgenic animals has demonstrated that blocking the formation of TNF-α inhibits the progression of arthritis [Rankin, E. C.; Choy, E. H.; Kassimos, D.; Kingsley, G. H.; Sopwith, A. M.; Isenberg, D. A.; Panayi, G. S. Br. J. Rheumatol. 1995, 34, 334; Pharmaprojects, 1996, Therapeutic Updates 17 (Oct.), au197-M2Z]. This observation has recently been extended to humans as well [“TNF-α in Human Diseases”, Current Pharmaceutical Design, 1996, 2, 662].
Numerous small molecule TACE inhibitors have been disclosed, as reviewed in “TNF-α Converting Enzyme (TACE) as a Therapeutic Target”, [Skotnicki, J. S.; Levin, J. I.; Ann. Reports Med. Chem., 2003, 38, 153]. The biology of inhibition of TACE by small molecule inhibitors has also been described [Newton, R. C.; Solomon, K. A.; Covington, M. B.; et al. Ann. Rheum. Dis. 2001, 60, iii25]. In addition the therapeutic potential of inhibitors of TACE has been reviewed [Duffy, M. J.; Lynn, D. J.; Lloyd, A. T.; O'Shea, C. M.; Thromb. Haemost. 2004, 89, 622; Lowe, C.; Exp. Opin. Ther. Patents, 1998, 8, 1309; Newton, R. C.; DeCicco, C. P.; J. Med. Chem. 1999, 42, 2295. Reinhold, A. M.; Curr. Drug Targets-Inflammation & Allergy, 2002, 1, 377]. Although a variety of TACE inhibitors are known, many of these molecules are peptidic and peptide-like which suffer from bioavailability and pharmacokinetic problems. In addition, many of these molecules are non-selective, being potent inhibitors of matrix metalloproteinases and, in particular, MMP-1. Inhibition of MMP-1 (collagenase 1) and/or MMP-14 has been postulated to cause joint pain in clinical trials of MMP inhibitors [Scrip, 1998, 2349, 20; Peterson, J. T.; Heart Failure Reviews, 2004, 9, 63; Renkiewicz, R.; Qiu, L.; Lesch, C.; Arthritis and Rheumatism, 2003, 48, 1742]. Selective, orally bioavailable non-peptide inhibitors of TACE would thus be highly desirable for the treatment of the disease states discussed above.